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- PDB-3me6: Crystal structure of cytochrome 2B4 in complex with the anti-plat... -

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Basic information

Entry
Database: PDB / ID: 3me6
TitleCrystal structure of cytochrome 2B4 in complex with the anti-platelet drug clopidogrel
ComponentsCytochrome P450 2B4
KeywordsOXIDOREDUCTASE / P450 / cytochrome P450 2B4 / monooxygenase / membrane protein / CYP 2B4 / CYP LM2
Function / homology
Function and homology information


unspecific monooxygenase / aromatase activity / iron ion binding / heme binding / endoplasmic reticulum membrane
Similarity search - Function
Cytochrome P450, E-class, group I, CYP2B-like / Cytochrome P450, E-class, group I / Cytochrome p450 / Cytochrome P450 / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Clopidogrel / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 2B4
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.1 Å
AuthorsGay, S.C. / Roberts, A.G. / Maekawa, K. / Talakad, J.C. / Hong, W.X. / Zhang, Q. / Stout, C.D. / Halpert, J.R.
Citation
Journal: Biochemistry / Year: 2010
Title: Structures of cytochrome P450 2B4 complexed with the antiplatelet drugs ticlopidine and clopidogrel.
Authors: Gay, S.C. / Roberts, A.G. / Maekawa, K. / Talakad, J.C. / Hong, W.X. / Zhang, Q. / Stout, C.D. / Halpert, J.R.
#1: Journal: J.Biol.Chem. / Year: 2006
Title: Structure of microsomal cytochrome P450 2B4 complexed with the antifungal drug bifonazole: insight into P450 conformational plasticity and membrane interaction.
Authors: Zhao, Y. / White, M.A. / Muralidhara, B.K. / Sun, L. / Halpert, J.R. / Stout, C.D.
#2: Journal: J.Biol.Chem. / Year: 2004
Title: Structure of mammalian cytochrome P450 2B4 complexed with 4-(4-chlorophenyl)imidazole at 1.9 {angstrom} resolution: Insight into the range of P450 conformations and coordination of redox partner binding.
Authors: Scott, E.E. / White, M.A. / He, Y.A. / Johnson, E.F. / Stout, C.D. / Halpert, J.R.
#3: Journal: Proc.Natl.Acad.Sci.USA / Year: 2003
Title: An open conformation of mammalian cytochrome P450 2B4 at 1.6 A resolution.
Authors: Scott, E.E. / He, Y.A. / Wester, M.R. / White, M.A. / Chin, C.C. / Halpert, J.R. / Johnson, E.F. / Stout, C.D.
#4: Journal: Biochemistry / Year: 2007
Title: Structural and thermodynamic consequences of 1-(4-chlorophenyl)imidazole binding to cytochrome P450 2B4.
Authors: Zhao, Y. / Sun, L. / Muralidhara, B.K. / White, M.A. / Stout, C.D. / Halpert, J.R.
#5: Journal: Biochemistry / Year: 2009
Title: Crystal Structures of Cytochrome P450 2B4 in Complex with the Inhibitor 1-Biphenyl-4-methyl-1H-imidazole: Ligand-Induced Structural Response through Alpha-Helical Repositioning
Authors: Gay, S.C. / Sun, L. / Maekawa, K. / Halpert, J.R. / Stout, C.D.
History
DepositionMar 31, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 15, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Oct 6, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 2B4
B: Cytochrome P450 2B4
C: Cytochrome P450 2B4
D: Cytochrome P450 2B4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)220,43012
Polymers216,6764
Non-polymers3,7538
Water2,378132
1
A: Cytochrome P450 2B4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,1073
Polymers54,1691
Non-polymers9382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 2B4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,1073
Polymers54,1691
Non-polymers9382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Cytochrome P450 2B4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,1073
Polymers54,1691
Non-polymers9382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Cytochrome P450 2B4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,1073
Polymers54,1691
Non-polymers9382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)234.490, 234.490, 57.320
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number143
Space group name H-MP3
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C
41D

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLY / Beg label comp-ID: GLY / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: 6 / Auth seq-ID: 28 - 492 / Label seq-ID: 9 - 473

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB
3CC
4DD

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Components

#1: Protein
Cytochrome P450 2B4 / CYPIIB4 / Cytochrome P450 isozyme 2 / Cytochrome P450 LM2 / Cytochrome P450 type B0 / Cytochrome P450 type B1


Mass: 54169.082 Da / Num. of mol.: 4
Mutation: E2A, G22K, H23K, P24T, K25S, A26S, H27K, R29K, H226Y
Source method: isolated from a genetically manipulated source
Details: Deleted residues 3-21, E2A, G22K, H23K, P24T, K25S, A26S, H27K, R29K, 4x Cterm His tag
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: CYP2B4 / Plasmid: PKK / Production host: Escherichia coli (E. coli) / Strain (production host): TOPP3 / References: UniProt: P00178, unspecific monooxygenase
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-CGE / Clopidogrel / methyl (2S)-(2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanoate / Clopidogrel


Mass: 321.822 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H16ClNO2S / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 132 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAUTHORS INDICATE THAT THERE IS AN ERROR IN THE SEQUENCE DATABASE REFERENCE AT RESIDUE 221

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 4.2 Å3/Da / Density % sol: 70.71 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 4.2
Details: 20% (w/v) PEG 8000, 0.2 M NaCl and 0.1 M phosphate-citrate, pH 4.2, vapor diffusion, sitting drop, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Nov 7, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 3.1→76.755 Å / Num. all: 62529 / Num. obs: 62529 / % possible obs: 97.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4 % / Rmerge(I) obs: 0.13 / Rsym value: 0.13 / Net I/σ(I): 4.7
Reflection shellResolution: 3.1→3.18 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.432 / Mean I/σ(I) obs: 3.5 / Num. unique all: 9259 / Rsym value: 0.432 / % possible all: 98.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 33.25 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.95 Å76.75 Å
Translation2.95 Å76.75 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.9data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
Blu-Icedata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1SUO

1suo


Resolution: 3.1→76.75 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.885 / WRfactor Rfree: 0.237 / WRfactor Rwork: 0.181 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.857 / SU B: 14.228 / SU ML: 0.258 / SU Rfree: 0.378 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R Free: 0.378 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.234 3169 5.1 %RANDOM
Rwork0.178 ---
all0.181 62529 --
obs0.181 62516 97.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 111.96 Å2 / Biso mean: 42.197 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å2-0.03 Å20 Å2
2---0.06 Å20 Å2
3---0.1 Å2
Refinement stepCycle: LAST / Resolution: 3.1→76.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14882 0 256 132 15270
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.02215506
X-RAY DIFFRACTIONr_angle_refined_deg1.9362.01321050
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.11651848
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.62322.542716
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.993152567
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.32515143
X-RAY DIFFRACTIONr_chiral_restr0.1320.22276
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02112015
X-RAY DIFFRACTIONr_mcbond_it0.8641.59300
X-RAY DIFFRACTIONr_mcangle_it1.715215092
X-RAY DIFFRACTIONr_scbond_it2.40436206
X-RAY DIFFRACTIONr_scangle_it4.2674.55958
Refine LS restraints NCS

Ens-ID: 1 / Number: 3718 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDTypeRms dev position (Å)Weight position
1ALOOSE POSITIONAL0.235
2BLOOSE POSITIONAL0.285
3CLOOSE POSITIONAL0.245
4DLOOSE POSITIONAL0.335
1ALOOSE THERMAL1.0510
2BLOOSE THERMAL1.1810
3CLOOSE THERMAL1.1210
4DLOOSE THERMAL1.2510
LS refinement shellResolution: 3.1→3.181 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 214 -
Rwork0.233 4483 -
all-4697 -
obs--97.43 %

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